Preparation of risperidone

ABSTRACT

The present invention is directed to the novel forms of risperidone, designated Form A, Form B and Form E. Methods for their preparation are also disclosed. The present invention also relates to processes for making risperidone. Pharmaceutical compositions containing the new forms of risperidone and methods of using them are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of provisional applicationserial No. 60/225,361, filed Aug. 14, 2000; and provisional applicationserial No. 60/243,263, filed Oct. 25, 2000. Both of these applicationsare incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel polymorphic forms ofrisperidone. The present invention also relates to methods of makingpolymorphic forms of risperidone.

BACKGROUND OF THE INVENTION

[0003] RISPERDAL® (risperidone) is an antipsychotic agent belonging to anew chemical class, the benzisoxazole derivatives. The chemicaldesignation is3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

[0004] U.S. Pat. No. 4,804,663, the contents of which are incorporatedby reference, describes a synthesis of risperidone. Risperidone may beprepared by condensation of the following two intermediates,6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (Compound I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II) in dimethylformamide (DMF) in basic conditions (Na₂CO₃ orK₂CO₃) with catalytic amount of potassium iodide (KI). The cruderisperidone product (III) is crystallized from a mixture of DMF andisopropanol with an overall yield of 46%.

[0005] Polymorphism is the occurrence of different crystalline forms ofa single compound and it is a property of some compounds and complexes.Thus, polymorphs are distinct solids sharing the same molecular formula,yet each polymorph may have distinct physical properties. Therefore, asingle compound may give rise to a variety of polymorphic forms whereeach form has different and distinct physical properties, such asdifferent solubility profiles, different melting point temperaturesand/or different x-ray diffraction peaks. Since the solubility of eachpolymorph may vary, identifying the existence of pharmaceuticalpolymorphs is essential for providing pharmaceuticals with predicablesolubility profiles. It is desirable to investigate all solid stateforms of a drug, including all polymorphic forms, and to determine thestability, dissolution and flow properties of each polymorphic form.Polymorphic forms of a compound can be distinguished in a laboratory byX-ray diffraction spectroscopy and by other methods such as, infraredspectrometry. For a general review of polymorphs and the pharmaceuticalapplications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J.K. Haleblian and W. McCrone, J Pharm. Sci., 58, 911 (1969); and J. K.Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which areincorporated herein by reference.

SUMMARY OF THE INVENTION

[0006] An object of the processes of the present invention is to providemore efficient and quicker methods for making pure risperidone. We havenow found that the synthesis of risperidone from compounds I and II candone in acetonitrile and isopropanol, without using DMF, to give animproved and higher yield of about 75%.

[0007] The present invention provides a process for the preparation ofrisperidone from the following two intermediates,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II) in acetonitrile.

[0008] It has also been found that the crude risperidone can beefficiently crystallized in high yield from an alcohol, for example,isopropanol, butanol, ethanol, or methanol; or from a ketone, forexample, acetone or ethyl methyl ketone, without the need of using DMF,which is harmful to humans and is a very difficult solvent to remove.

[0009] Polymorphs of risperidone are mentioned in the Summary Basis ofApproval (SBA) of New Drug Application 20-272 and 20-588, however theSBA does not identify them by recognized methods of crystal structureidentification such as x-ray diffraction.

[0010] The present invention also provides forms of risperidonedesignated risperidone Form A, Form B and Form E.

[0011] The present invention further provides a process for makingrisperidone comprising reacting Compound I with Compound II to formcrude risperidone (III) in a solvent selected from the group consistingof acetonitrile, isopropanol, methyl ethyl ketone and iso-butanol.

[0012] In another embodiment, the crude risperidone is recrystallizedfrom an alcohol; a mixture of alcohols; a mixture of water and alcohol;or from a ketone, e.g., acetone. In another embodiment, the alcohol isselected from the group consisting of methanol, ethanol, isopropanol,propanol, butanol, sec-butanol, iso-butanol and t-butanol. In anotherembodiment, the alcohol is isopropanol. In another embodiment, thealcohol is acetonitrile. In another embodiment, the alcohol isisopropanol. In another embodiment, the alcohol is iso-butanol. Inanother embodiment, the ketone is acetone. In another embodiment, theacetone is methyl ethyl ketone.

[0013] The present invention also provides risperidone Form A which ischaracterized by x-ray powder diffraction peaks at 14.2±0.2, 21.3±0.2degrees two-theta. The present invention also provides risperidone FormA of further characterized by x-ray powder diffraction peaks at10.6±0.2, 11.4±0.2, 16.4±0.2, 18.9±0.2, 19.9±0.2, 22.5±0.2, 23.3±0.2,25.4±0.2, 27.6±0.2, 29.0±0.2 degrees two-theta.

[0014] The present invention also provides a risperidone polymorph thatis characterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 1.

[0015] The present invention also provides risperidone Form B which ischaracterized by x-ray powder diffraction peaks at 14.0±0.2 and 21.7±0.2degrees two-theta.

[0016] The present invention also provides a risperidone polymorph thatis characterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 2.

[0017] The present invention also provides risperidone Form B which isfurther characterized by x-ray powder diffraction peaks at 10.8±0.2,11.9±0.2, 12.6±0.2, 14.0±0.2, 17.5±0.2, 18.3±0.2, 19.9±0.2, 21.0±0.2,21.7±0.2 degrees two-theta.

[0018] The present invention also provides risperidone Form E which ischaracterized by x-ray powder diffraction peaks at 16.5±0.2,21.7±0.2degrees two-theta.

[0019] The present invention also provides risperidone Form E which isfurther characterized by x-ray powder diffraction peaks at 16.5±0.2,12.6±0.2, 21.7±0.2, 15.6±0.2, 17.0±0.2, 18.4±0.2, 19.1±0.2, 21.3±0.2,24.0±0.2, 24.9±0.2, 27.0±0.2 degrees two-theta.

[0020] The present invention also provides a risperidone polymorph thatis characterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 3.

[0021] The present invention also provides a process for preparingrisperidone Form B comprising the steps of: dissolving risperidone in asubstantially water soluble alcohol having 1 to 4 carbon atoms where theratio of risperidone to alcohol is about 1:7.5 to about 1:9; addingwater to facilitate precipitation; and isolating risperidone Form B.

[0022] The present invention also provides a process for preparingrisperidone Form B comprising the steps of: dissolving risperidone inchloroform; adding cyclohexane or hexane to facilitate precipitation;and isolating risperidone Form B.

[0023] The present invention also provides a process for preparingrisperidone Form B comprising the steps of: dissolving risperidone in anaqueous solution of HCl; adding an aqueous solution of Na₂CO₃; andisolating risperidone Form B.

[0024] The present invention also provides a process for preparingrisperidone Form A comprising the steps of: dissolving risperidone in anorganic solvent selected from the group consisting of dimethylformamide,tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol,methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethylsulfoxide, iso-butanol, and ethyl acetate or mixtures thereof; heatingthe solvent to reflux; cooling the solvent to facilitate precipitation;and isolating risperidone Form A.

[0025] The present invention also provides a process for preparingrisperidone Form A comprising the steps of: dissolving risperidone indichloromethane; adding cyclohexane or hexane to facilitateprecipitation; and isolating risperidone Form A.

[0026] The present invention also provides a method for preparingrisperidone Form A comprising the step of: heating risperidone Form B ata temperature of about 25° C. to about 80° C. for a time sufficient toinduce to formation of risperidone Form A; and isolating risperidoneForm A. In another embodiment, the heating takes place under reducedpressure or at atmospheric pressure. In another embodiment, thetemperature is about 80° C. In another embodiment, the time for heatingis about 16 to about 20 hours.

[0027] The present invention also provides a process for preparingrisperidone Form E comprising the steps of: dissolving risperidone inisopropanol where the ratio of risperidone to isopropanol is about 1:12;adding water to facilitate precipitation; and isolating risperidone FormE.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028]FIG. 1 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form A.

[0029]FIG. 2 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form B.

[0030]FIG. 3 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form E.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Synthesis of Risperidone

[0032] The present invention provides new processes for preparingrisperidone from the following two intermediates,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(II) using acetonitrile, isopropanol, iso-butanol, or methyl ethylketone as the solvent, which eliminates the need to use DMF as asolvent. By the methods of the present invention, risperidone isprepared by adding,3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H1-pyrido[1,2-a]pyrimidin-4-one(Compound II or “the chlorine derivative”);6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I or “thepiperidine derivative”); sodium carbonate; and potassium iodide (66 mg)into a flask containing the solvent isopropanol, acetonitrile, methylethyl ketone or iso-butanol. Preferably, the Compound I and Compound IIare present in a ratio of about 1:1. The reaction mixture is then heatedby methods known in the art, such as, by placing the flask in an oilbath which is heated from about 60° C. to about 85° C., and the reactionis allowed to reflux for a time sufficient to complete the formation ofrisperidone, about 9 hours to overnight. Preferably, the reactionmixture is heated to about 60° C. to about 67° C. Preferably thereaction is heated for about 9 hours when the solvent is isopropanol.Preferably the reaction mixture is heated overnight when the solvent ismethyl ethyl ketone or iso-butanol. Preferably the reaction is heatedfor about 17 hours when the solvent is acetonitrile. Upon completion ofthe reaction, the mixture is cooled by methods known in the art toinduce the precipitation of risperidone.

[0033] The resulting precipitated risperidone is filtered and the filtercake is washed in the filter with a small amount of isopropanol, acetoneor a mixture of acetone and water. The filter cake is then slurried,filtered and easily dried by conventional methods to give cruderisperidone in a yield of about 63 to 74% yield. The present methodeliminates the difficult step of removing DMF from the cruderisperidone.

[0034] The present invention also relates to new processes forrecrystallizing crude risperidone from; an alcohol, such as, methanol,ethanol, isopropanol, propanol, butanol, sec-butanol and t-butanol; amixture of alcohols containing any combination of, methanol, ethanol,isopropanol, propanol, butanol, sec-butanol and t-butanol; or a mixtureof water and alcohol where the alcohol is one or more of the followingalcohols, methanol, ethanol, isopropanol, propanol, butanol, sec-butanoland t-butanol. The present recrystallization eliminates the use of thedifficult to remove and potentially harmful solvent DMF. Preferably, thesolvent is isopropanol. By the methods of the present invention, cruderisperidone is recrystallized by dissolving the crude risperidone in asolvent which is hot. Preferably, the solvent is heated to reflux.Preferably the crude risperidone and solvent are present in a ratio ofabout 10 to about 15, more preferably the ratio is about 11 to 13, mostpreferably the ratio is about 11.5 to about 12.5. Preferably the solventis isopropanol. The hot mixture is then filtered hot and allowed to coolwhere upon purified risperidone precipitates. The mixture is filtered byconventional methods to give high purity risperidone with a purity ofabout 99.7 to about 99.8%. The overall yield of the present method ofsynthesis and recrystallization of risperidone is about 60 to about 63%.

[0035] The present invention also provides new processes forrecrystallizing crude risperidone from a solvent that is a ketone, suchas, acetone. The present recrystallization eliminates the use of thedifficult to remove and potentially harmful solvent DMF. Preferably, thesolvent is acetone. By the methods of the present invention, cruderisperidone is recrystallized by dissolving the crude risperidone in aketone, which is hot. Preferably, the ketone is heated to reflux.Preferably the crude risperidone and solvent are present in a ratio ofabout 25 to about 40, more preferably the ratio is about 28 to about 32.Preferably the solvent is acetone. The hot mixture is then filtered hotand allowed to cool where upon purified risperidone precipitates. Themixture is filtered by conventional methods to give high purityrisperidone with a purity of about 99.7 to about 99.8%. The overallyield of the present method of synthesis and recrystallization ofrisperidone is about 60 to about 63%.

[0036] Risperidone Form A

[0037] The present invention also relates to a novel risperidonecrystalline form designated Form A and processes for making risperidoneForm A. Risperidone Form A is characterized by unique strong powderx-ray diffraction peaks at 14.2±0.2, and 21.3±0.2 degrees two-theta andmedium intensity peaks at 10.6±0.2, 11.410.2, 16.4±0.2, 18.9±0.2,19.9±0.2, 22.5±0.2, 23.3±0.2, 27.6±0.2, 25.4±0.2, and 29.0±0.2 degreestwo-theta.

[0038] Another aspect of this invention is a method of preparingrisperidone Form A. In the method of preparing risperidone Form A,risperidone Form A is crystallized from risperidone at the refluxtemperature of an organic solvent, such as, DMF, tetrahydrofuran (THF),acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol,absolute ethanol, acetonitrile, toluene, dimethyl sulfoxide (DMSO),iso-butanol or ethyl acetate. By the methods of the present invention,risperidone is added to in a minimum amount of organic solvent byheating the mixture to facilitate dissolution of the risperidone. Uponcomplete dissolution of the risperidone, the solution is left to cool toroom temperature to induce the precipitation of risperidone Form A.After the solution has reached room temperature, it is further cooled inan ice bath and then filtered to isolate risperidone Form A. Suitablevolumes of solvent required for the present methods are listed below inExample 11 and in Table 1.

[0039] Another aspect of this invention is a method of preparingrisperidone Form A; or a mixture of risperidone Form A and other formsof risperidone, including risperidone Form B, by dissolving risperidonein dichloromethane and adding cyclohexane or hexane to induceprecipitation. By the methods of the present invention, risperidone isdissolved in dichloromethane in a ratio of about 1 to about 9. Hexane orcyclohexane is then added until a cloudy dispersion is formed. Therisperidone Form A is then isolated by filtration.

[0040] Another aspect of this invention is a method of preparingrisperidone Form A by heating risperidone Form B. By the methods of thepresent invention, risperidone Form A is prepared by heating risperidoneForm B, or a mixture of risperidone Form A and B at temperatures aboveroom temperature, preferably at about 80° C., under either reducedpressure or at atmospheric pressure, for a period of several minutes toseveral hours, preferably 16-20 hours. One embodiment of the presentmethod for preparing risperidone Form A is heating risperidone Form B,or a mixture of risperidone Form B and risperidone Form A, at 80° C.overnight, under reduced pressure or at atmospheric pressure, andisolating the resulting crystals of risperidone Form A. An alternativemethod of preparing risperidone Form A by heating risperidone Form Bincludes, heating risperidone Form B in a differential scanningcalorimeter, at the rate of 5 to 20 degrees per minute, to yieldrisperidone Form A.

[0041] Risperidone Form B

[0042] The present invention also relates to a novel crystalline form ofrisperidone, denominated risperidone Form B. Risperidone Form B ischaracterized by unique strong powder x-ray diffraction peaks at14.0±0.2 and 21.7±0.2 degrees two-theta, and medium peaks at 10.8±0.2,11.9±0.2, 12.6±0.2, 17.5±0.2, 18.3±0.2, 19.9±0.2, 21.0±0.2, 21.3±0.2degrees two-theta, and is well distinguished from risperidone Form A.The presence of risperidone Form B in a mixture with risperidone Form Ais detected by the appearance mainly of the strongest peaks at 21.7±0.2,17.5±0.2, 18.4±0.2, and also by the other peaks which appear at11.9±0.2, 12.6±0.2 degrees two theta.

[0043] The DSC thermogram of risperidone Form B is characterized by asolid-solid transition to risperidone Form A detected in a smallendotherm at 164° C. followed by a small exotherm and a meltingendotherm of risperidone Form A at 171° C.

[0044] Another aspect of this invention is a method of preparingrisperidone Form B by dissolving risperidone in an alcohol having 1 to 4carbon atoms, followed by the addition of water to facilitate theprecipitation of risperidone Form B. Preferably the ratio of risperidoneto alcohol is about 1:7.5 to about 1:9. Preferably the alcohol isethanol or methanol.

[0045] Another aspect of this invention is a method of preparingrisperidone Form B pure or in a mixture with another form ofrisperidone, such as, risperidone Form A, which includes dissolvingrisperidone in a hot solution of aqueous HCl followed by the addition ofaqueous Na₂CO₃ to induce precipitation of risperidone Form B. By themethods of the present invention, risperidone is added to 0.5 N HCl in aratio of about 1:6. Water is added in an amount equal to about twothirds the volume of HCl used. The solution is heated to inducedissolution of the risperidone. Sodium carbonate is then added until apH of about 8 is reached, to facilitate precipitation. The solution iscooled and risperidone Form B is isolated by filtration.

[0046] Another aspect of this invention is a method of preparingrisperidone Form B pure or in a mixture with another form of risperidonesuch as risperidone Form A, wherein risperidone is dissolved inchloroform followed by the addition of cyclohexane or hexane tofacilitate precipitation. By the methods of the present invention,risperidone is dissolved in chloroform in a ratio of about 1:6 followedby the addition of hexane of cyclohexane in an amount sufficient toproduce a cloudy dispersion. The risperidone Form B is then isolatedupon filtration.

[0047] Risperidone Form E

[0048] The present invention also relates to a novel crystalline form ofrisperidone, denominated risperidone Form E. Risperidone Form E ischaracterized by typical strong x-ray peaks at 16.5±0.2, 21.7±0.2degrees two-theta, and medium x-ray peaks at 12.6±0.2, 15.6±0.2,17.0±0.2, 18.4±0.2, 19.1±0.2, 21.3±0.2, 24.0±0.2, 24.9±0.2, 27.0±0.2degrees two-theta

[0049] Another aspect of this invention is a method of preparingrisperidone Form E. By the methods of the present invention, risperidoneis dissolved in isopropanol in a ratio of about 1 to 12. Water is thenadded until a cloudy dispersion is formed thereby facilitating theprecipitation of risperidone Form E. Risperidone Form E is isolated uponfiltration of the dispersion.

[0050] In accordance with the present invention, these new forms ofrisperidone may be prepared as pharmaceutical compositions that areparticularly useful for the management of the manifestations ofpsychotic disorders. Such compositions comprise one of the new forms ofrisperidone with pharmaceutically acceptable carriers and/or excipientsknown to one of skill in the art.

[0051] Preferably, these compositions are prepared as medicaments to beadministered orally, or intravenously. Suitable forms for oraladministration include tablets, compressed or coated pills, dragees,sachets, hard or gelatin capsules, sub-lingual tablets, syrups andsuspensions. While one of ordinary skill in the art will understand thatdosages will vary according to the indication, age of the patient, etc.,generally polymorphic forms of risperidone of the present invention willbe administered at a daily dosage of about 4 to about 16 mg per day, andpreferably about 4 to about 8 mg per day.

EXAMPLES

[0052] The present invention will now be further explained in thefollowing examples. However, the present invention should not beconstrued as limited thereby.

Methods

[0053] Conditions for obtaining Powder X-ray Diffraction (PXRD)patterns: The powder X-ray diffraction patterns were obtained by methodsknown in the art using a Philips X-ray powder diffractometer, PhillipsGenerator TW 1830; Goniometer PW3020; MPD Control PW3710; X-Ray tubewith Cu target anode; Monochromator proportional counter; Divergenceslits 1°, Receiving slit 0.2 mm, Scatter slit 1°; 40 KV, 30 mA; andScanning speed step 0.05 degrees to 2 degrees/min.

[0054] The differential scanning calorimeter thermograms were obtainedby methods known in the art using a DSC Mettler 821 Star^(e). The weightof the samples was about 3-5 mg. The temperature range of scans was 30°C.-250° C. at a rate of 10C/min. Samples were purged with nitrogen gasat a flow rate of 40 mL/min. Standard 40 μl aluminum crucibles were usedhaving lids with three small holes.

Example 1 Synthesis of Risperidone

[0055] Isopropanol (20 mL),3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II)(“the chlorine derivative”)(2.63 g, 10 mmoles, 1 eq.),6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I)(“thepiperidine derivative”) (2.17 g, 10 mmoles, 1 eq.), sodium carbonate(3.18 g, 30 mmoles, 3 eq.), and potassium iodide (66 mg) were added to a100 mL round bottom flask and stirred with a magnetic stir bar. Theflask was placed in an oil bath at 80° C. and allowed to reflux for 9hours. The flask was then cooled in an ice bath and the contents wasfiltered. The filter cake was washed in the filter with a small amountof isopropanol. The filter cake was then slurried 3 times in 20 mL ofwater and filtered. The resulting slurry was dried to give 3 g ofmaterial in 73% yield. The slurry was recrystallized by dissolving in 37mL of boiling isopropanol, filtered hot and allowed to cool and filteredto give material which had a purity of 99.7% and an overall yield of60%.

Example 2 Synthesis of Risperidone

[0056] The same materials and method as in Example 1 with the exceptionbeing that methyl ethyl ketone (MEK) (15 mL) was used instead of 20 mLof isopropanol. The flask was put in an oil bath at 79-83° C. overnight,cooled, filtered and washed with acetone and water to give 2.19 g, 53%yield.

Example 3 Synthesis of Risperidone

[0057] The same materials and method as in Example 1 with the exceptionbeing that 20 mL of acetonitrile was used instead of 20 mL ofisopropanol. The flask was put in an oil bath for 17 hours at 79-83° C.,then put in the freezer for 2 hours, filtered, and the filter cakewashed with acetone until the filtrate had no color. The filter cake wasthen slurried in 25 mL water 3 times and filtered and dried to give 3.03g, 74% yield, of crude risperidone. The crude risperidone wasrecrystallized from 35 mL of isopropanol, filtered hot, cooled, filteredand dried to give 2.47 g of risperidone, 60% overall yield, 99.8% pureby HPLC.

Example 4 Synthesis of Risperidone

[0058] The same materials and method as in Example 1 with the exceptionbeing that 20 mL of acetonitrile was used instead of 20 mL ofisopropanol. The flask was put in an oil bath for 17 hours at 79-83° C.,then put in the freezer for 2 hours, filtered, and the filter cakewashed with acetone until the filtrate had no color. The filter cake wasthen slurried in 25 mL water 3 times and filtered and dried to give 3.03g, 74% yield, of crude risperidone. The crude risperidone wasrecrystallized from 75 mL of acetone, filtered hot, cooled, filtered anddried to give 2.25 g of risperidone, 60% overall yield, 99.9% pure byHPLC.

Example 5 Synthesis of Risperidone

[0059] The same materials and method as in Example 1 with the exceptionbeing that 20 mL of iso-butanol was used instead of 20 mL of isopropanolfollowed by stirring in an oil bath at 78° C. over night. Risperidonewas isolated in 63% yield.

Example 6 Preparation of Risperidone Form B

[0060] Risperidone (5.3 g) was dissolved in chloroform (30 mL).Cyclohexane (280 mL)was slowly added to the solution until a cloudydispersion was formed. The suspension was filtered. The filtrate,analyzed by PXRD, contained risperidone Form B. Further heatingovernight at 80° C. under reduced pressure produced risperidone Form A,which was confirmed by PXRD analysis.

Example 7 Preparation of Risperidone Form B

[0061] Risperidone (5.0 g) was dissolved in 30 mL chloroform. Hexane(250 mL) was added to the solution until a cloudy dispersion was formed.The suspension was filtered. The isolated filtrate, analyzed by PXRD,contained risperidone Form B. Further heating of the filtrate overnightat 80° C. under reduced pressure produced risperidone Form A, which wasconfirmed by PXRD analysis.

Example 8 Preparation of Risperidone Form B

[0062] Risperidone (5.3 g) was dissolved in 40 ml ethanol. Water (100mL) was added to the solution until a cloudy dispersion was formed. Theresulting suspension was filtered. The isolated filtrate, analyzed byPXRD, contained risperidone Form B. Further heating of the filtrateovernight at 80° C., under reduced pressure, produced risperidone FormA, which was confirmed by PXRD analysis.

Example 9 Preparation of Risperidone Form B

[0063] Risperidone (5.0 g) was dissolved in methanol (45 mL). Water (70ml) was added to the solution until a cloudy dispersion was formed. Thesuspension was filtered. The isolated filtrate, analyzed by PXRD,contained risperidone Form B. Further heating of the filtrate overnightat 80° C., under reduced pressure, produced risperidone Form A, whichwas confirmed by PXRD analysis.

Example 10 Preparation of Risperidone Form B in Water

[0064] Risperidone (6 g) was dissolved at room temperature in 60 mL of0.5 N HCl and water (40 mL) was added. The solution was heated in aboiling water bath and stirred with a magnetic stir bar. Concentratedaqueous sodium carbonate was added portion-wise to the solution tofacilitate precipitation until a pH of approximately 8 was attained. Aprecipitate was formed. After cooling to room temperature, the mixturewas cooled in an ice bath and filtered to give a mixture of risperidoneForm A and risperidone Form B in an 82% yield.

Example 11 Preparation of Risperidone Form A by Crystallization inOrganic Solvents

[0065] Risperidone (6 g) was added portion-wise and dissolved in aminimum amount of solvent by heating in a boiling water bath (about 95°C.). Suitable solvents and the corresponding suitable volumes are listedbelow in Table 1. Solvents having a boiling point lower than 95° C. wereheated to their boiling point. The solutions were left to cool to roomtemperature to facilitate precipitation of risperidone Form A. Themixture was then further cooled in an ice bath and then filtered. Theprecipitate was analyzed by PXRD and found to be risperidone Form A.TABLE 1 Preparation of Risperidone Form A The volumes of solvents usedper 6 grams of Risperidone DMF:  40 ml iso-butanol:  35 ml THF:  40 mlAcetone: 200 ml Benzene:  26 ml methyl ethyl ketone:  70 ml absoluteethanol:  35 ml n-butanol:  45 ml Methanol:  40 ml Toluene:  45 mlAcetonitrile: 100 ml DMSO: 100 ml ethyl acetate: 150 ml Isopropanol: 100ml

Example 12 Preparation of Risperidone Form A

[0066] Risperidone (5.6 g) was dissolved in 50 mL dichloromethane.Cyclohexane (170 mL) was added to the solution until a cloudy dispersionwas formed. The resulting suspension was filtered. The isolatedfiltrate, analyzed by PXRD, contained risperidone Form A and a minorquantity of risperidone Form B.

Example 13 Preparation of Risperidone Form A

[0067] Risperidone (5.1 g) was dissolved in 30 mL dichloromethane.n-Hexane (150 mL) was added to the solution to facilitate precipitationuntil a cloudy dispersion was formed. The resulting suspension wasfiltered. The filtrate, analyzed by PXRD, contained risperidone Form Aand a minor quantity of risperidone Form B.

Example 14 Preparation of Risperidone Form E

[0068] Risperidone (5 g ) was dissolved in 60 mL isopropanol. Water (950mL) was added to the solution to facilitate precipitation until a cloudydispersion was formed. The suspension was filtered. The filtrate,analyzed by PXRD, contained risperidone Form E.

[0069] Although certain presently preferred embodiments of the inventionhave been described herein, it will be apparent to those skilled in theart to which the invention pertains that variations and modifications ofthe described embodiment may be made without departing from the spiritand scope of the invention. Accordingly, it is intended that theinvention be limited only to the extent required by the appended claimsand the applicable rules of law.

What is claimed is:
 1. A process for making risperidone comprising thesteps of reacting compound (I)

with compound (II)

to form crude risperidone (III)

in a solvent selected from the group consisting of acetonitrile,isopropanol, methyl ethyl ketone and iso-butanol.
 2. The process ofclaim 1, further comprising the steps of recrystallizing cruderisperidone from an alcohol, a mixture of alcohols, or a mixture ofwater and alcohol.
 3. The process of claim 2, wherein the alcohol isselected from the group consisting of methanol, ethanol, isopropanol,propanol, butanol, sec-butanol, and t-butanol.
 4. The process of claim3, wherein the alcohol is isopropanol.
 5. The process of claim 1,wherein the solvent is acetonitrile.
 6. The process of claim 1, whereinthe solvent is isopropanol.
 7. The process of claim 1, wherein thesolvent is methyl ethyl ketone.
 8. The process of claim 1, wherein thesolvent is iso-butanol.
 9. The process of claim 1, further comprisingthe steps of recrystallizing crude risperidone from a ketone.
 10. Theprocess of claim 1 wherein the ketone is acetone.
 11. Risperidone Form Awhich is characterized by x-ray powder diffraction peaks at 14.2±0.2,21.3±0.2 degrees two-theta.
 12. The risperidone Form A of claim 11 whichis further characterized by x-ray powder diffraction peaks at 10.6±0.2,11.4±0.2, 16.4±0.2, 18.9±0.2, 19.9±0.2, 22.5±0.2, 23.3±0.2, 25.4±0.2,27.6±0.2, 29.0±0.2 degrees two-theta.
 13. A risperidone polymorph thatis characterized by a powder x-ray diffraction pattern substantially asdepicted in FIG.
 1. 14. Risperidone Form B which is characterized byx-ray powder diffraction peaks at 14.0±0.2 and 21.7±0.2 degreestwo-theta.
 15. The risperidone Form B of claim 14 which is furthercharacterized by x-ray powder diffraction peaks at 10.8±0.2, 11.9±0.2,12.6±0.2, 14.0±0.2, 17.5±0.2, 18.3±0.2, 19.9±0.2, 21.0±0.2, 21.7±0.2degrees two-theta.
 16. A risperidone polymorph that is characterized bya powder x-ray diffraction pattern substantially as depicted in FIG. 2.17. Risperidone Form E which is characterized by x-ray powderdiffraction peaks at 16.5±0.2, 21.7±0.2 degrees two-theta.
 18. Therisperidone Form E of claim 17 which is further characterized by x-raypowder diffraction peaks at 16.5±0.2, 12.6±0.2, 21.7±0.2, 15.6±0.2,17.0±0.2, 18.4±0.2, 19.1±0.2, 21.3±0.2, 24.0±0.2, 24.9±0.2, 27.0±0.2degrees two-theta.
 19. A risperidone polymorph that is characterized bya powder x-ray diffraction pattern substantially as depicted in FIG. 3.20. A process for preparing risperidone Form B comprising the steps of:(a) dissolving risperidone in a water soluble alcohol having 1 to 4carbon atoms where the ratio of risperidone to alcohol is about 1:7.5 toabout 1:9; (b) adding water to facilitate precipitation; and (c)isolating risperidone Form B.
 21. A process for preparing risperidoneForm B comprising the steps of: (a) dissolving risperidone inchloroform; (b) adding cyclohexane or hexane to facilitateprecipitation; and (c) isolating risperidone Form B.
 22. A process forpreparing risperidone Form B comprising the steps of: (a) dissolvingrisperidone in an aqueous solution of HCl; (b) adding aqueous Na₂CO₃ tofacilitate precipitation; and (c) isolating risperidone Form B.
 23. Aprocess for preparing risperidone Form A comprising the steps of: (a)dissolving risperidone in an organic solvent selected from the groupconsisting of dimethylformamide, tetrahydrofuran, acetone, benzene,ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol,acetonitrile, toluene, dimethyl sulfoxide, iso-butanol, and ethylacetate; (b) heating the solvent to reflux; (c) cooling the solvent tofacilitate precipitation; and (d) isolating risperidone Form A.
 24. Aprocess for preparing risperidone Form A comprising the steps of: (a)dissolving risperidone in dichloromethane; (b) adding cyclohexane orhexane to facilitate precipitation; and (c) isolating risperidone FormA.
 25. A process for preparing risperidone Form E comprising the stepsof: (a) dissolving risperidone in isopropanol where the ratio ofrisperidone to isopropanol is about 1:12; (b) adding water to facilitateprecipitation; and (c) isolating risperidone Form E.
 26. A process forpreparing risperidone Form A comprising the steps of: (a) heatingrisperidone Form B at a temperature of about 25° C. to about 80° C. fora time sufficient to induce to formation of risperidone Form A; and (b)isolating risperidone Form A.
 27. The process of claim 26 wherein theheating takes place under reduced pressure or at atmospheric pressure.28. The process of claim 26 wherein the temperature is about 80° C. 29.The process of claim 26 wherein the time is about 16 to about 20 hours.